A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells

Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature (Impact Factor: 41.46). 09/2010; 467(7312):214-7. DOI: 10.1038/nature09337
Source: PubMed


Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern-recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known. Dendritic cells are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. Here we show that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine.

  • Source
    • "examining innate immune recognition of HIV-1 have utilized cell-free particles and characterized responses occurring in dendritic cells or macrophages (Gao et al., 2013; Hayashi et al., 2010; Jakobsen et al., 2013; Lahaye et al., 2013; Manel et al., 2010; Sun et al., 2013; Yan et al., 2010). More recently , attention has focused on resting CD4 T cells in lymphoid tissues, which are mostly non-permissive for productive HIV infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The progressive depletion of CD4 T cells underlies clinical progression to AIDS in untreated HIV-infected subjects. Most dying CD4 T cells correspond to resting nonpermissive cells residing in lymphoid tissues. Death is due to an innate immune response against the incomplete cytosolic viral DNA intermediates accumulating in these cells. The viral DNA is detected by the IFI16 sensor, leading to inflammasome assembly, caspase-1 activation, and the induction of pyroptosis, a highly inflammatory form of programmed cell death. We now show that cell-to-cell transmission of HIV is obligatorily required for activation of this death pathway. Cell-free HIV-1 virions, even when added in large quantities, fail to activate pyroptosis. These findings underscore the infected CD4 T cells as the major killing units promoting progression to AIDS and highlight a previously unappreciated role for the virological synapse in HIV pathogenesis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell Reports
  • Source
    • "Dendritic cells are therefore not permissive to a full HIV-1 replication cycle, even when SAMHD1 restriction is suppressed. An initial study suggested that this is because the virus is detected by innate sensors acting after viral integration and detecting a complex between the HIV-1 gag protein and the cellular gag-binding cofactor CypA (Manel et al., 2010). However, a more recent study from this group proposed that, in fact, if SAMHD1 is inactivated with Vpx, then the cytoplasmic DNA sensor cGAS detects HIV-1 reverse transcription products, leading to activation of innate signaling cascades and the maturation of the dendritic cells (Lahaye et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV-1 was recognized as the cause of AIDS in humans in 1984. Despite 30 years of intensive research, we are still unraveling the molecular details of the host-pathogen interactions that enable this virus to escape immune clearance and cause immunodeficiency. Here we explore a series of recent studies that consider how HIV-1 interacts with the cell-autonomous innate immune system as it navigates its way in and out of host cells. We discuss how these studies improve our knowledge of HIV-1 and host biology as well as increase our understanding of transmission, persistence, and immunodeficiency and the potential for therapeutic or prophylactic interventions.
    Full-text · Article · Jul 2014 · Cell Host & Microbe
  • Source
    • "In contrast to HIV-1, HIV-2 naturally infects DCs [20], and this function depends on counteraction of SAMHD1 by Vpx, a viral protein not present in HIV-1 [17], [18]. Vpx is incorporated into HIV-2 particles and is released after viral fusion, inducing degradation of host cell SAMHD1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. Paradoxically, in the case of HIV-1, DCs might contribute to viral pathogenesis through trans-infection, a mechanism that promotes viral capture and transmission to target cells, especially after DC maturation. In this review, we highlight recent evidence identifying sialyllactose-containing gangliosides in the viral membrane and the cellular lectin Siglec-1 as critical determinants for HIV-1 capture and storage by mature DCs and for DC-mediated trans-infection of T cells. In contrast, DC-SIGN, long considered to be the main receptor for DC capture of HIV-1, plays a minor role in mature DC-mediated HIV-1 capture and trans-infection.
    Full-text · Article · Jul 2014 · PLoS Pathogens
Show more